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During exercise, genes for FGF2 receptor are also activated (demonstrated on
neutrophils [ 45 ]). However, there are signs that concentration of FGF2 is
exercise- independent [ 46 , 47 ]. FGF seem to be effective in initiating neoangio-
genesis in hypoxic or ischemic tissues [ 48 ].- Angiopoietins: are members of the vascular endothelial growth factor family as
the only known growth factors largely specific for vascular endothelium. They
act via endothelial cell-specific receptors known as the Ties [ 49 , 50 ]. There is
another group of angiopoietin-like proteins, where at least some of their mem-
bers (ANGPTL2, ANGPTL8) are found guilty of proinflammatory and proath-
erogenic actions with effect in propagation of coronary artery disease
(cardiovascular disease) [ 51 – 53 ]. We dispose with evidence that levels of these
angiopoietins-lige proteins are acutely reduced after physical exercise. A sus-
tained reduction in circulating levels could contribute to the chronic beneficial
cardiometabolic effects in patients with coronary artery disease [ 51 ].- Endothelial NO: the competency of endothelial NO production is very impor-
tant in permitting vascular remodeling through arteriogenesis in skeletal muscle
arteries. Recognition that chronic endurance exercise with regular bouts of
increased laminar flow along the endothelium upregulates endothelial nitric
oxide synthase (eNOS) implies that there is an improved responsiveness for
vascular remodeling, compared with sedentary individuals [ 25 , 54 , 55 ]. Activity
of eNOS in endothelial cells is triggered by pro-angiogenic factors, mainly
VEGF. Higher occurrence of NO during physical activity has an antiapoptotic
effect that could potentially underlie exercise-related beneficial effects on car-
diovascular diseases via increased production and circulating numbers of endo-
thelial stem cells [ 56 ].- Circulating micro-RNAs (c-miRNAs): they are short, nonprotein coding RNA
molecules. miRNA-126 is vascular endothelium specific and its levels are
increased during and shortly after endurance training [ 57 , 58 ]. miRNA-126, a
miRNA located within the egfl7 gene (protein EGFL7 was described as a novel
endothelial cell-derived factor involved in the regulation of the spatial arrange-
ment of cells during vascular tube assembly) may be related to exercise-induced
cardiac angiogenesis and vascular integrity, by indirect regulation of the VEGF
pathway and direct regulation of its targets that converged in an increase in
angiogenic pathways, such as MAPK and PI3K/Akt/eNOS [ 58 , 59 ]. However,
experiments in 2015 on human umbilical vein endothelial cells showed exactly
the opposite results: transfection with a miR-126 significantly downregulated
VEGFA mRNA levels and transfection with a miR-126 inhibitor significantly
upregulated VEGFA mRNA levels [ 60 ]. Equally, miRNA-129-1 and miRNA- 133
act, to our knowledge, as anti-angiogenic factors [ 61 ], as well as miRNA- 26a [ 62 ].- Anti-angiogenic factor pigment epithelium-derived factor (PEDF): human
adult cardiac myocytes and fibroblasts constitutively secrete PEDF and inhibit
VEGF-induced sprouting. PEDF expression is down-regulated by low oxygen
levels [ 63 ], thus there is a theory, that PEDF plays a negative feedback-role in
regular endurance exercise.7 Physical Exercise Can Spur Beneficial Neoangiogenesis andflMicrovasculature...